Conversion of big endothelin-1 and characterization of its contractile effects on isolated human placental arteries.
OBJECTIVE
To study the conversion of human big endothelin-1 (bigET-1) to endothelin-1 (ET-1) and to characterize contractile ET-1 receptors in human placental arteries.


METHODS
BigET-1 was incubated with artery membranes and the formation of ET-1 was investigated. ET-1 and bigET-1-induced contractile responses were studied in the absence or presence of the metalloprotease inhibitor phosphoramidon, the ET(A)-receptor antagonist BQ 123, or the ETB-receptor antagonists IRL 1038 and RES 701-1.


RESULTS
The artery membranes hydrolysed bigET-1 to ET-1 through a partly phosphoramidon-sensitive pathway. The contractile responses to ET-1 and bigET-1 were similar, with pEC50% values of 8.1 +/- 0.2 and 7.8 +/- 0.1, respectively (NS; n = 17). Phosphoramidon decreased pEC50% for bigET-1-evoked contractions (p < 0.05; n = 8), without affecting the response to ET-1. A Schild plot of BQ 123 effects on ET-1 and bigET-1-induced contractions resulted in identical pA2 values and a slope of 0.56 +/- 0.2 and 0.47 +/- 0.01, respectively. IRL 1038 and RES 701-1 did not affect the contractile responses.


CONCLUSIONS
BigET-1-evoked contractions in isolated human placental arteries depend on a rapid and metalloprotease-dependent hydrolytic conversion to ET-1, which in turn causes a, mainly ETA-receptor-mediated, contraction.
Hanson
G C
GC
Department of Clinical Pharmacology, Lund University Hospital, Sweden.
Wide-Swenson
D
D
Andersson
K E
KE
Lindberg
B F
BF
D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D016232:Endothelins / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014469:Umbilical Arteries / Q000187:drug effects / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D006020:Glycopeptides; D008565:Membrane Proteins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011498:Protein Precursors; D014361:Trypsin Inhibitors; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon